Interleukin (IL)-1β is a culprit of adipose tissue inflammation, which in turn causes systematic inflammation and insulin resistance in obese individuals. IL-1β is mainly produced in monocytes and macrophages and marginally in adipocytes, through cleavage of the inactive pro-IL-1β precursor by caspase-1, which is activated via the NLRP3 inflammasome complex. The nuclear factor-κB (NF-κB) transcription factor is the master regulator of inflammatory responses. Brindle berry (Garcinia cambogia) has been widely used as health products for treating obesity and related metabolic disorders, but its active principles remain unclear. We previously found a series of polyisoprenylated benzophenones from brindle berry with anti-inflammatory activities. In this study we investigated whether 14-deoxygarcinol (DOG), a major polyisoprenylated benzophenone from brindle berry, alleviated adipose tissue inflammation and insulin sensitivity in high-fat diet fed mice. The mice were administered DOG (2.5, 5 mg · kg⁻¹ · d⁻¹, i.p.) for 4 weeks. We showed that DOG injection dose-dependently improved insulin resistance and hyperlipidemia, but not adiposity in high-fat diet-fed mice. We found that DOG injection significantly alleviated adipose tissue inflammation via preventing macrophage infiltration and pro-inflammatory polarization of macrophages, and adipose tissue fibrosis via reducing the abnormal deposition of extracellular matrix. In LPS plus nigericin-stimulated THP-1 macrophages, DOG (1.25, 2.5, 5 μM) dose-dependently suppressed the activation of NLRP3 inflammasome and NF-κB signaling pathway. We demonstrated that DOG bound to and activated the deacetylase Sirtuin 2, which in turn deacetylated and inactivated NLRP3 inflammasome to reduce IL-1β secretion. Moreover, DOG (1.25, 2.5, 5 μM) dose-dependently mitigated inflammatory responses in macrophage conditioned media-treated adipocytes and suppressed macrophage migration toward adipocytes. Taken together, DOG might be a drug candidate to treat metabolic disorders through modulation of adipose tissue remodeling.

白细胞介素 (IL)-1β 是脂肪组织炎症的罪魁祸首，它反过来会导致肥胖个体发生系统性炎症和胰岛素抵抗。IL-1β 主要在单核细胞和巨噬细胞中产生，少量在脂肪细胞中产生，通过 caspase-1 裂解无活性的 pro-IL-1β 前体，caspase-1 通过 NLRP3 炎性体复合物激活。核因子-κB (NF-κB) 转录因子是炎症反应的主要调节因子。斑纹浆果（Garcinia cambogia) 已被广泛用作治疗肥胖和相关代谢紊乱的保健品，但其活性成分仍不清楚。我们之前从斑纹浆果中发现了一系列具有抗炎活性的聚异戊二烯化二苯甲酮。在这项研究中，我们研究了 14-脱氧藤黄醇 (DOG)，一种来自斑纹浆果的主要聚异戊二烯化二苯甲酮，是否能减轻高脂肪饮食喂养小鼠的脂肪组织炎症和胰岛素敏感性。给小鼠施用 DOG（2.5、5 mg·kg ^-1  ·d ^-1, ip) 4 周。我们表明，注射 DOG 剂量依赖性地改善胰岛素抵抗和高脂血症，但不会改善高脂肪饮食喂养的小鼠的肥胖。我们发现注射 DOG 通过防止巨噬细胞浸润和巨噬细胞的促炎性极化显着减轻脂肪组织炎症，并通过减少细胞外基质的异常沉积显着减轻脂肪组织纤维化。在 LPS 加尼日利亚菌素刺激的 THP-1 巨噬细胞中，DOG（1.25、2.5、5 μM）剂量依赖性地抑制 NLRP3 炎性体和 NF-κB 信号通路的激活。我们证明了 DOG 结合并激活了去乙酰化酶 Sirtuin 2，后者又使 NLRP3 炎性体去乙酰化和失活以减少 IL-1β 的分泌。此外，DOG (1.25, 2.5, 5 μM)剂量依赖性地减轻巨噬细胞条件培养基处理的脂肪细胞中的炎症反应，并抑制巨噬细胞向脂肪细胞的迁移。总之，DOG 可能是通过调节脂肪组织重塑来治疗代谢紊乱的候选药物。